The SIV model provides the best available system to investigate the pathogenesis of neurological disease in humans with AIDS encephalopathy. HIV-1 infection in humans is frequently accompanied by neurological disease; HIV isolates from the brain are macrophage-tropic and exhibit a limited degree of viral heterogeneity. In the brain HIV is found in cells of macrophage lineage (microglia). SIV encephalitis in monkeys closely resembles the changes observed in the CNS of both children and adults with AIDS encephalopathies. In the SIV model, use of genetically defined viruses make it possible to investigate the viral genes that contribute to cell-tropism and gene expression in specific cells in the CNS. The hypothesis to be tested in these experiments is that a tropism for macrophages is a prerequisite for both HIV and SIV to infect cells in the CNS. However, a further selection for virus replication in specific CNS cells is necessary for infection and the progression of disease. We will examine whether SIV infection of these cells alters the expression of cellular genes that leads to cellular activation and cell loss. Multiple in vivo passages of cloned lymphocyte-tropic SIV lead to the isolation of macrophage and neurotropic SIV; infectious recombinant clones have been constructed that reflect this phenotype and will be used in these studies. The role of macrophage-tropic/neurotropic viruses in the development of CNS disease will be examined and the molecular basis of replication of these viruses in primary monkey macrophages, and brain derived microglia cells will be studied. It will be determined if virus replication in the brain, measured by quantitating both viral DNA and RNA levels, correlates with the severity of disease. The state of virus gene expression (i.e. latent or active) will be studied in differentiated cells derived from the CNS. The effect of SIV infection on the expression of a cellular cytokine gene (TNFalpha) and the expression of cell adhesion molecules in macrophages and microglia will be examined in vitro and in tissues from infected monkeys. These studies complement and utilize the animal studies done in Project 1; infected cells and tissue from infected monkeys will be used in all AIMS of this project. Studies on the role of adhesion molecules in the virus biology in Project 2 will be further studied in AIM 5 of this project to determine if infection with SIV alters the expression of these adhesion molecules.